Chiral Aziridination of Olefins Using a Chiral Sulfinamide as the Nitrogen Source

Abstract

Chiral aziridination of cyclic α-bromoenones is achieved by the use of the lithium salt of (S _S)-(+)-p-toluenesulfinamide, which leads to products with diastereomeric excesses in the range of 30-65% using a simple protocol. A key factor associated with chiral induction is the incorporation of the reacting olefin in a cycle, indicating the importance of conformational restriction in the reacting double bond.

Key words

aminations - chirality - cyclizations - enones - Michael additions

References and Notes

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15

This compound is commercially available from Sigma-Aldrich Co (http://www.sigmaaldrich.com).

17

CCDC 741870 contains the crystallographic data which can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [e-mail]. ac.uk, or by contacting CCDC, UK; fax: [phone].

21

Full coordinates and other information about the calculations can be found via the following digital repository entries: 10042/to-2308, 10042/to-23010, 10042/to-2311, 10042/to-2312, 10042/to-2314 and 10042/to-2315, resolved as e.g. http://dx.doi.org/10042/to-2308. An interactive version of this figure can be viewed via the HTML version of this article.

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Typical Experimental Procedure for Aziridination
To a dry THF solution of 2-bromocyclohex-2-en-1-one (2a, 0.286 mmol), under nitrogen atmosphere and protected from light at -78 ˚C, was added the lithium salt of chiral sulfinamide 1 (0.858 mmol) and the reaction allowed to reach r.t. After 30 min the solvent was removed under reduced pressure and the residue dissolved in EtOAc, washed with aq NH₄Cl (10%), and after drying and solvent removal, the remaining residue was purified via silica gel PTLC (EtOAc-n-hexane, 1:1) to afford a mixture of the title aziridines 3Aa (major)/3Ba (minor); yield 62%. Separation of both diastereomers was achieved by 2 × PTLC of the mixture.
Compound 3Aa(major): mp 70-71 ˚C (EtOAc-n-hexane); [α]_D ^²³ +64.6 (c 0.99, CHCl₃).
Compound 3Ba(minor): mp 90-91 ˚C (EtOAc-n-hexane); [α]_D ^²³ +89.4 (c 1.44, CHCl₃). ^¹H NMR (400 MHz, CDCl₃; 3Aa/3Ba = 77:23): δ = 7.60 (2 H, d, J = 8.2 Hz, minor), 7.55 (2 H, d, J = 8.2 Hz, major), 3.23 (1 H, d, J = 6.3 Hz, minor), 3.13 (1 H, d, J = 6.3 Hz, major), 3.06 (1 H, d, J = 6.3 Hz, major), 2.94 (1 H, d, J = 6.3 Hz, minor). MS (CI): m/z (%) = 249 (100) [M⁺]. Anal. Calcd for C₁₃H₁₅NO₂S: C, 62.62; H, 6.06; N, 5.62. Found: C, 62.31; H, 6.34; N, 5.74.
Compound 3b: oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.59 (2 H, d, J = 8.1 Hz, minor), 7.55 (2 H, d, J = 8.1 Hz, major), 3.08 (1 H, d, J = 6.3 Hz, major), 2.94 (1 H, d, J = 6.4 Hz, minor), 2.85 (1 H, d, J = 6.4 Hz, minor), 2.77 (1 H, d, J = 6.3 Hz, major). HRMS: m/z calcd for C₁₅H₁₉NO₂S: 277.11365; found: 277.11344. Anal. Calcd for C₁₅H₁₉NO₂S: C, 64.95; H, 6.90; N, 5.05. Found: C, 65.27; H, 7.16; N, 4.95.
Compound 3c: mp 64-65 ˚C (EtOAc-n-hexane). ^¹H NMR (400 MHz, CDCl₃): δ = 3.79 (2 H, d, J = 5.4 Hz, minor), 3.64 (1 H, d, J = 5.6 Hz, major), 3.41 (1 H, d, J = 6.2 Hz, major), 3.30 (1 H, d, J = 6.2 Hz, minor). MS (EI): m/z (%) = (1.1) 402 [M + 1]⁺. Anal. Calcd for C₂₅H₂₃NO₂S: C, 74.78; H, 5.77; N, 3.49. Found: C, 75.16; H, 5.74; N, 3.37.
Compound 3d (major): mp 97-98 ˚C (Et₂O-n-hexane); [α]_D ^²³ +22.0 (c 0.90, CHCl₃).
Compound 3d (minor): mp 105-106 ˚C (Et₂O-n-hexane); [α]_D ^²³ +12.4 (c 2.03, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.62 (2 H, d, J = 8.2 Hz, minor), 7.54 (2 H, d, J = 8.2 Hz, major), 3.56 (1 H, m, minor), 3.53 (1 H, m, major), 3.11 (1 H, d, J = 4.3 Hz, major), 3.08 (1 H, d, J = 4.3 Hz, minor). HRMS-FAB: m/z calcd for C₁₂H₁₄NO₂S: 236.074526; found: 236.075172.
Compound 3f: oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.60 (2 H, d, J = 7.8 Hz, minor), 7.54 (2 H, d, J = 7.8 Hz, major), 3.23 (1 H, d, J = 4.4 Hz, minor), 3.21 (1 H, d, J = 4.4 Hz, major), 3.13 (1 H, d, J = 4.4 Hz, major), 3.10 (1 H, d, J = 4.4 Hz, minor). MS (FI): m/z (%) =(100) 263 [M⁺]. Anal. Calcd for C₁₄H₁₇NO₂S: C, 63.85; H, 6.51; N, 5.32. Found: C, 62.95; H, 6.81; N, 5.17.
Compound 3g: mp 92-93 ˚C (Et₂O-n-pentane). ^¹H NMR (400 MHz, CDCl₃): δ = 7.61 (2 H, d, J = 8.1 Hz, minor), 7.56 (2 H, d, J = 8.1 Hz, major), 3.13 (1 H, J = 7.7, 1.5 Hz, major), 3.06 (1 H, m, minor), 2.97 (1 H, dd, J = 7.7, 4.6 Hz, major), 2.80 (1 H, m, minor). MS (EI): m/z (%) =(18) 263 [M⁺]. Anal. Calcd for C₁₄H₁₇NO₂S: C, 63.85; H, 6.51; N, 5.32. Found: C, 62.62; H, 6.72; N, 5.29.
Compound 3h: diasteriomeric mixture (1:1), mp 69-71 ˚C, 77-80 ˚C (EtOAc). ^¹H NMR (400 MHz, CDCl₃): δ = 2.81
(1 H, d, J = 4.1 Hz), 2.79 (1 H, d, J = 7.3 Hz), 2.71 (1 H, d, J = 6.9 Hz), 2.24 (1 H, d, J = 3.7 Hz). HRMS (EI): m/z calcd for C₁₆H₁₅NO₂S: 285.08235; found: 285.083598. Anal. Calcd for C₁₆H₁₅NO₂S: C, 67.34; H, 5.30; N, 4.91. Found: C, 67.34; H, 5.30; N, 4.91.
Compounds 3i: 3Ai: mp 103-105 ˚C (EtOAc); [α]_D ^²³ -15.1 (c 3.30, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 3.91 (1 H, dd, J = 6.5, 3.3 Hz), 2.89 (1 H, d, J = 3.3 Hz), 2.66 (1 H, d, J = 6.5 Hz). Anal. Calcd for C₁₅H₁₅NO₃S₂: C, 56.05; H, 4.70; N, 4.36. Found: C, 55.87; H, 4.76; N, 4.38. 3Bi: mp 120-121 ˚C (EtOAc); [α]_D ^²³ +7.4 (c 2.04, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 3.70 (1 H, dd, J = 6.3, 3.2 Hz), 2.75 (1 H, d, J = 6.3 Hz), 2.43 (1 H, br d); the attribution to 3Ai and 3Bi may be reversed. HRMS (EI): m/z calcd for C₁₅H₁₅NO₃S₂: 321.04933; found: 321.04958.
Oxidation of 3Aa/3Ba
To a solution of 3Aa/3Ba (0.2 mmol) was added MCPBA (0.4 mmol), and after 18 h at r.t. the solvent was removed and the enantiomeric mixture of 4Aa/4Ba isolated (yield 99%); ee 53% from ^¹H NMR (400 MHz, CDCl₃): δ = 3.45 (1 H, H₂) split by addition of Eu(hfc)₃.